Current potential health benefits of sulforaphane

Sulforaphane [SFN: 1-isothiocyanato-4-(methylsulfinyl)butane] belongs to the isothiocyanate class of phytochemicals. Glucoraphanin, a glucosinolate precursor of SFN, is a glucosinolate found in cruciferous vegetables such as broccoli, cabbage, cauliflower, and kale. All glucosinolates are composed of a basic structure consisting of a β-D-thioglucose group, a sulfonated oxime group, and an amino acid-derived side chain. Glucosinolates are activated by enzyme-dependent hydrolysis to their respective isothiocyanates. SFN (molecular formula C6H11NOS2) is the biologically active isothiocyanate produced by the metabolism of glucoraphanin by the enzyme myrosinase (Fahey et al., 2015). SFN is one of the most frequently studied plant-derived isothiocyanate organosulfur compounds. It has been reported to exhibit a wide range of biological effects including antioxidant (Fahey and Talalay, 1999), antimicrobial (Johansson et al., 2008), anticancer (Amjad et al., 2015), anti-inflammatory (Greaney et al., 2016), anti-aging (Sikdar et al., 2016), neuroprotective (Tarozzi et al., 2013), and antidiabetic (Lee et al., 2012). SFN shows a range of biological activities and health benefits in humans, has been found to be a very promising chemopreventive agent against not only a variety of cancers such as breast, prostate, colon, skin, lung, stomach, and bladder but also against cardiovascular and neurodegenerative diseases and diabetes (Yang et al., 2016). In this present study, we reviewed the most recent studies on the biological and pharmacological activities of SFN (Table 1).

The chemopreventive effect of SFN is associated with its inhibition of histone deacetylase (HDAC) activity, which attenuates lung cancer growth. These findings suggest that SFN may be a promising therapeutic agent for lung cancer by the inhibition of HDAC. Jiang et al., 2016 Treatment with SFN could be useful for improving cognitive function in patients with cirrhosis with minimal or clinical hepatic encephalopathy. Hernández-Rabaza et al., 2016 The use of SFN as a protective agent against ultraviolet damage is a novel application, and it appears to be a very promising emerging ingredient in anti-aging drugs and cosmetics. Sikdar et al., 2016 SFN protects cardiomyocytes from hypoxia/reoxygenation injury in vitro, most likely by activating the silent information regulator 1 (Sir1) pathway and subsequently inhibiting endoplasmic reticulum (ER) stress-dependent apoptosis. Li et al., 2016 SFN epigenetically stimulates osteoblast activity and diminishes osteoclast bone resorption, thereby shifting the bone homeostasis balance to favor bone acquisition, mitigation of bone resorption, or both in vivo. Thus, SFN is a member of a new class of epigenetic compounds that could be considered novel strategies to counteract osteoporosis. Thaler et al., 2016 SFN remarkably suppressed cell growth and enhanced cell death in chemoresistant xenografts in the nude mouse model. Collectively, the present study suggests that the clinical efficacy of temozolomide-based chemotherapy of temozolomide-resistant glioblastoma may be improved by combination therapy with SFN. Lan et al., 2016 SFN ameliorates the progression of high cholesterol diet-induced atherosclerotic lesions and vascular dysfunction, possibly via its lipid-lowering and antioxidant effects and suppression of nuclear factor-kappa B (NF-κB)-mediated inflammation. Shehatou and Suddek, 2016 SFN is a beneficial supplement that may be useful for reducing microglialmediated neuroinflammation and the oxidative stress associated with aging.
Townsend and Johnson, 2016 SFN exerts protective effects against lipopolysaccharide-induced acute lung injury through the nuclear factor-erythroid 2-related factor 2 (NFE2L2)/antioxidant response element (ARE) pathway. Thus, SFN may be a potential candidate for use in the treatment of acute lung injury. Qi et al., 2016 The SFN-mediated modification of chromatin composition and structure associated with target gene expression provides a new mechanism by which dietary phytochemicals may exert their chemopreventive activity. Abbas et al., 2016 Dietary supplementation with broccoli sprout extract containing the SFN precursor, glucoraphanin, is likely to be highly effective in improving liver function through the reduction of oxidative stress. Kikuchi et al., 2015 Glucoraphanin supplementation for a few weeks is safe but may not be sufficient to produce changes in breast tissue tumor biomarkers. Future studies using larger sample sizes should evaluate alternative dosage regimens to improve dietary SFN strategies for breast cancer chemoprevention. Atwell et al., 2015 SFN suppresses the inflammatory response by inhibiting the NF-ĸB signaling pathway in a rat model of focal cerebral ischemia and, therefore, may be a potential therapeutic agent for the treatment of cerebral ischemia injury.

Key findings Reference
SFN may inhibit human colon cancer progression and cancer cell angiogenesis by inhibiting hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression. Taken together, these results indicate that SFN is a new and potent chemopreventive drug candidate for treating patients with human colon cancer. Kim et al., 2015 SFN attenuated the cytotoxicity of cadmium selenide (CdSe) quantum dots (QDs) in both human hepatocytes and the mouse liver, and this protection was associated with the induction of the Nrf2 pathway and autophagy. Wang et al., 2015 SFN activates DNA methylation-silenced tumor suppressor genes in breast cancer cells. Therefore, SFN may be a supportive adjuvant therapy with the anticancer drug, clofarabine and, therefore, might increase its effectiveness in solid tumor treatment.

Lubecka-Pietruszewska et al., 2015
The potential usefulness of the blockade of bronchoconstrictor hyperresponsiveness in some types of asthmatics by phytochemicals such as SFN has been reported. Brown et al., 2015 The antioxidant effects of SFN in mouse plasma and hippocampal formations is evidenced by the increased catalase and superoxide dismutase activity, as well as the increased adenosine triphosphate (ATP) production by hippocampal mitochondria. Furthermore, these effects likely underlie SFN's anticonvulsant mechanisms of action.

Carrasco-Pozo et al., 2015
In vehicle-treated mice, ischemia/reperfusion (I/R) injury produced a marked thinning of the inner retinal layers, which, however, appeared to be significantly reduced following SFN treatment. Therefore, SFN may be beneficial in the treatment of retinal disorders associated with I/R injury. Ambrecht et al., 2015 SFN reversed the iron-induced decrease in the mitochondrial fission protein, DNM1L, as well as hippocampal synaptophysin levels, leading to a recovery of the associated recognition memory impairment. These findings suggest that SFN should be further investigated as a potential agent for the treatment of cognitive deficits associated with neurodegenerative disorders. SFN was also found to efficiently scavenge hydrogen peroxide by converting it into water. Thus, the mechanism of action of SFN as an excellent antioxidant has been revealed.
Prasad and Mishra, 2015 SFN protected the vascular endothelial cells against lysophosphatidylcholineinduced injury by enhancing the antioxidative capabilities mediated by Nrf-2 translocation.

Li et al., 2015
Daily administration of free SFN shows promise in managing biochemical recurrences of prostate cancer after radical prostatectomy.
Cipolla et al., 2015 SFN demonstrates pleiotropic behavior, owing to its effects on different cellular targets, suggesting a potential role in preventing or counteracting multifactorial neurodegenerative disorders such as Alzheimer's disease (AD). Angeloni et al., 2015 SFN reduced the liver oxidative stress induced by I/R injury. Furthermore, histological injury of the liver was reduced by SFN administration. However, SFN showed no significant effects on the remote organ injuries induced by IR. Oguz et al., 2015 SFN plays a protective role against acetaminophen-mediated hepatotoxicity through antioxidant effects mediated by heme oxygenase-1 (HO-1) induction. SFN has preventive actions against oxidative stress-mediated liver injury.

Key findings Reference
SFN ameliorated experimental diabetic nephropathy, at least in part, via the glycogen synthase kinase 3-beta (GSK3β)/Fyn (tyrosine kinase)/Nrf2 signaling pathway. Shang et al., 2015 Combined treatment of cells with SFN and 3-methyladenine (3-MA) proved to be effective in decreasing cell viability, through a mechanism that may involve early SFN-induced autophagy, followed by induction of apoptosis and inhibition of autophagy by 3-MA. Horwacik et al., 2015 SFN showed more potent renoprotection against I/R injury than ischemic preconditioning (Ipre) did, and this effect might involve synergism between them at the molecular but not functional level. Shokeir et al., 2015 SFN stimulates suicidal erythrocyte death or eryptosis, which may, at least partially, be due to the stimulation of Ca (2+) entry and ceramide formation.
Alzoubi et al., 2015 SFN stimulates proteasome activity and autophagy in normal and Hutchinson-Gilford progeria syndrome (HGPS) fibroblast cultures. Specifically, SFN enhances progerin clearance by autophagy and reverses the phenotypic changes that are the hallmarks of HGPS. Therefore, SFN is a promising therapeutic strategy for children with HGPS. Gabriel et al., 2015 SFN has the potential to prevent cardiac hypertrophy by downregulating the transcription factors GATA-binding factor 4/6 (GATA4/6) and mitogen-activated protein kinase (MAPK) signaling pathways. Kee et al., 2015 Both SFN and klotho, a protein with multiple pleiotropic effects associated with anti-aging, enhance the antioxidant defenses, which may protect against vascular smooth muscle cell dysfunction in age-related cardiovascular diseases. Rizzo et al., 2014 SFN showed protective effects against retinal I/R, which could be attributed, at least in part, to the activation of the Nrf2/HO-1 antioxidant pathway. Pan et al., 2014 SFN alleviates D-galactosamine/lipopolysaccharide-induced liver injury, possibly by exerting antioxidant, anti-inflammatory, and antiapoptotic effects and modulating certain antioxidant defense enzymes. Sayed et al., 2014 Dietary SFN is recognized to have low toxicity and was identified for its ability to reverse abnormalities associated with autism spectrum disorder. The abnormalities included oxidative stress and lowered antioxidant capacity, depressed glutathione synthesis, reduced mitochondrial function and oxidative phosphorylation, increased lipid peroxidation, and neuroinflammation. Singh et al., 2014 Blockade of the advanced glycation end product (AGE)-receptor for AGE (RAGE) axis in pericytes by SFN might be a novel therapeutic target for the treatment of diabetic retinopathy. Maeda et al., 2014 SFN ameliorates neurobehavioral deficits by reducing cholinergic neuron loss in the brains of AD-like mice, and the underlying mechanism may be associated with neurogenesis and aluminum load reduction. These findings suggest that the phytochemical, SFN has potential usefulness in AD therapy. Zhang et al., 2014 SFN-enhanced autophagy flux provided protection against prion-mediated neurotoxicity, which was regulated by adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling pathways in human neuronal cells. This data also suggests that SFN has potential value as a therapeutic tool in neurodegenerative disorders including prion diseases. Lee et al., 2014 SFN might set the stage for the development of a novel therapeutic principle that complements the growing armature against malignancies, which would encourage the exploration of its efficacy in a broader population of patients with leukemia. Fimognari et al., 2014 SFN has antitumor effects against bladder cancer cells mediated through a reactive oxygen species (ROS)-mediated intrinsic apoptotic pathway, which suggest that ER stress and Nrf2 may represent strategic targets for SFN-induced apoptosis.

Jo et al., 2014
Jo GH, Kim GY, Kim WJ, Park KY, Choi YH. Sulforaphane induces apoptosis in T24 human urinary bladder cancer cells through a reactive oxygen species-mediated mitochondrial pathway: the involvement of endoplasmic reticulum stress and the Nrf2 signaling pathway. Int J Oncol. 2014;45:1497-506.
Johansson NL, Pavia CS, Chiao JW. Growth inhibition of a spectrum of bacterial and fungal pathogens by sulforaphane, an isothiocyanate product found in broccoli and other cruciferous vegetables. Planta Med. 2008;74:747-50.